High levels of oncomiR-21 contribute to the senescence-induced growth arrest in normal human cells and its knock-down increases the replicative lifespan
| Autor: | Hanna Dellago, Erwin Tschachler, Carina Schreiner, Barbara Preschitz-Kammerhofer, Florian Gruber, Matthias Hackl, Marcel Scheideler, Markus Schosserer, Johannes Grillari, Rossella Monteforte, Matthias Wieser, Harald Kühnel, Regina Grillari-Voglauer, Martina Wei-Fen Chang, Lucia Terlecki-Zaniewicz, Klaus Fortschegger |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Senescence
CDK2 Cyclin-Dependent Kinase Inhibitor p21 Aging Down-Regulation Neovascularization Physiologic Apoptosis Biology Transfection Biochemistry Endocrinology Growth arrest Genetics Human Umbilical Vein Endothelial Cells cellular senescence Humans cdc25 Phosphatases RNA Small Interfering Molecular Biology Cells Cultured Cell Proliferation microRNA p21 Cyclin-Dependent Kinase 2 Cell Biology Original Articles hyperoncogenic signal CDC25A NFIB Cell biology Up-Regulation body regions MicroRNAs NFI Transcription Factors embryonic structures RNA Interference miR-21 |
| Zdroj: | Aging Cell |
| ISSN: | 1474-9726 1474-9718 |
| Popis: | Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo, their effect on their microenvironment and its double-edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age-associated diseases in mouse model systems. To characterize the role of miRNAs in cellular senescence of endothelial cells, we performed miRNA arrays from HUVECs of five different donors. Twelve miRNAs, comprising hsa-miR-23a, hsa-miR-23b, hsa-miR-24, hsa-miR-27a, hsa-miR-29a, hsa-miR-31, hsa-miR-100, hsa-miR-193a, hsa-miR-221, hsa-miR-222 and hsa-let-7i are consistently up-regulated in replicatively senescent cells. Surprisingly, also miR-21 was found up-regulated by replicative and stress-induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with miR-21 resulted in lower angiogenesis, and less cell proliferation mirrored by up-regulation of p21(CIP1) and down-regulation of CDK2. These two cell-cycle regulators are indirectly regulated by miR-21 via its validated direct targets NFIB (Nuclear factor 1 B-type), a transcriptional inhibitor of p21(CIP) (1) , and CDC25A, which regulates CDK2 activity by dephosphorylation. Knock-down of either NFIB or CDC25A shows a phenocopy of over-expressing miR-21 in regard to cell-cycle arrest. Finally, miR-21 over-epxression reduces the replicative lifespan, while stable knock-down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that miR-21 is the first miRNA that upon its knock-down extends the replicative lifespan of normal human cells. |
| Databáze: | OpenAIRE |
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